Ah Zwinderman

Telomere length loss due to smoking and metabolic traits

Human age‐dependent telomere attrition and telomere shortening are associated with several age‐associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length.

Common variants of multiple genes that control reverse cholesterol transport together explain only a minor part of the variation of HDL cholesterol levels

It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high‐density lipoprotein cholesterol (HDL‐C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL‐C‐related genes to variation of HDL‐C plasma levels. A well‐characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP‐binding cassette transporter A1, apolipoprotein A‐I and apolipoprotein‐E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol‐acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9–17.9%) of variation in HDL‐C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4–21.2%), and when 10 two‐way interactions were incorporated, this percentage rose to 25.2% (18.9–31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL‐C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL‐C plasma levels still have to be elucidated.

The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes

To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcomes.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

Introduction Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. Methods and results BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). Conclusion Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

Increased risk for ischaemic events is related to combined RAS polymorphism

OBJECTIVE To determine whether the angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT1R A1166C) gene polymorphism interact to increase the risk of ischaemic events, and whether this can be explained by the progression of angiographically defined coronary atherosclerosis. DESIGN Prospective defined substudy of the lipid lowering regression trial (REGRESS). SETTING University hospital. PATIENTS 885 male patients with stable coronary artery disease. MAIN OUTCOME MEASURES Incidence of ischaemic events during a two year follow up; serial quantitative coronary arteriography (mean segment diameter and minimum obstruction diameter) at baseline and after two years. RESULTS Patients who carried both the ACE-DD and AT1R-CC genotype had significantly more ischaemic events during the two year follow up than those carrying other genotype combinations (p = 0.035, Mantel-Haenszel test for linear association). There was no association between the two genotypes and mean segment diameter or minimum obstruction diameter at baseline or after two years. CONCLUSIONS The suggestion that ACE-DD and AT1R-CC genotypes interact to increase the risk of ischaemic events is confirmed. However, this increased risk was not accompanied by increased progression of angiographically defined coronary atherosclerosis.

An integrated evaluation of endothelial constitutive nitric oxide synthase polymorphisms and coronary artery disease in men

In the present study, we sought to evaluate the role of three polymorphisms in the ecNOS (endothelial constitutive nitric oxide synthase) gene in relation to the existence, severity and progression of CAD (coronary artery disease), MI (myocardial infarction) and the occurrence of ischaemia in a predominantly Caucasian population. Patients with CAD (n = 760) and age- and sex-matched population-based controls (n = 691) were genotyped for the -786T/C, E/D298 and 4a/b polymorphisms. Patients were randomized to pravastatin (40 mg) or placebo. Progression of atherosclerosis was evaluated by sequential angiography. Functionality was assessed by ST segment analysis of ambulant ECGs. The E298 (P = 0.003) and 4a (P = 0.001) alleles were associated with CAD. Furthermore, E298 (P = 0.009) and -786T (P = 0.022) alleles were associated with previous MI among patients, predominantly smokers. D/D298 homozygotes, but not -786T/C or 4a/4b mutants, had longer-lasting ischaemia than others (P < 0.05). We found no differences in progression of atherosclerosis, irrespective of pravastatin use. We conclude that the E/D298 polymorphism is most consistently associated with CAD, but not with progression of atherosclerosis. The E allele is associated with CAD and MI, whereas the D allele is associated with ischaemia.

Mortality in pulmonary arterial hypertension due to congenital heart disease: Serial changes improve prognostication

BACKGROUND Adult patients with pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) suffer from high mortality. This underlines the importance of adequate risk stratification to guide treatment decisions. Several baseline parameters are associated with mortality, however, their prognostic value may weaken after years of follow-up. Therefore we investigated the prognostic value of serial changes in standard clinical parameters in PAH-CHD. METHODS In this prospective observational cohort study we included consecutive PAH-CHD adults, between 2005 and 2016. Control visits to the outpatient clinic were standardized, including functional, biochemical and echocardiographic tests, according to the guidelines. The prognostic value of serial changes was determined with time-dependent Cox regression. RESULTS Ninety-two patients with PAH-CHD were included (age 43±15years, 34% male, 38% Down, 73% Eisenmenger). During a median follow-up of 6.0 (IQR 3.7-9.3) years, 35 (38%) patients died. Serial changes in World Health Organization functional classification (WHO-FC, HR 18.34 for onset class IV), six-minute walk distance (6-MWD, HR 0.65 per 50m), oxygen saturation at peak exercise (peak SaO2, HR 0.74 per 5%), NTproBNP (HR 2.25 per 1000ng/l) and echocardiographic right ventricular function (TAPSE, HR 0.80 per 0.5cm) significantly predicted mortality. Moreover, serial changes in these parameters were more potent predictors compared to baseline parameters, based on reduction in -2 log likelihood. CONCLUSIONS Serial changes in standard clinical parameters have more prognostic value compared to baseline parameters in PAH-CHD. Our results emphasize the importance of screening for serial changes since periodical assessment could guide treatment decisions to delay disease progression.

Angiographic endpoints in progression trials

The use of different angiographic criteria represents one of the reasons why the results of angiographic trials are difficult to compare. In principle, this is an avoidable problem and therefore a serious attempt at standardization should be made. This chapter reviews the criteria which have been used in trials using quantitative coronary angiography and presents a proposal for standardization.

Associations of major bleeding and recurrent myocardial infarction with the incidence and timing of mortality in patients with ST-segment elevation myocardial infarction

Purpose: The purpose of the current analysis was to investigate the temporal mortality pattern after recurrent MI (reMI) and severe bleeding in STEMI patients. Methods: From 1-1-2003 to 31-7-2008, 2002 patients were treated with primary PCI for STEMI and followed for the occurrence of recurrent MI and GUSTO severe bleeding. Hazard ratios for 4 year mortality for discrete time intervals after bleeding or reMI were calculated in a time-dependent, covariate adjusted Cox model. Results: After a reMI, the risk of subsequent mortality was high in the first days after the reMI, gradually decreased over time, but remained elevated long after the reMI (see table). After a bleeding, the risk of mortality was high in the first days after the bleeding, but rapidly decreased to non-significant. View this table: Table 1. Impact of recurrent MI and GUSTO severe bleeding on subsequent mortality to 4 years Conclusions: The occurrence of reMI and bleeding in the first year after STEMI are both associated with subsequent mortality. The risk implication of reMI however was greater and more sustained than that of severe bleeding.

Clinical efficacy and safety of pravastatin treatment in symptomatic patients — the REGRESS trial

Intensive lowering of serum cholesterol may retard progression of coronary atherosclerosis in selected groups of patients. However, in almost all studies, patients with a (nearly) normal serum cholesterol level as well as patients who were likely to undergo a cardiac revascularization procedure have been excluded from the trials. Thus, few data are available about the potential benefit of serum cholesterol reduction in the broad range of patients with coronary atherosclerosis and normal to moderately elevated serum cholesterol levels, who undergo various forms of treatment. The Regression Growth Evaluation Statin Study (REGRESS) addresses this group of patients.